Research Theme: This U54 Center will use translational research from brain to bedside as a tool for medication development in cocaine use disorder (CocUD). Preclinical and early phase I clinical PK/PD data will provide information for go/no-go decisions on phase 11-111 clinical trials for medications that have some promise for CocUD based on drug mechanisms and early preclinical data. The overall goal of this application is to create a center that can provide important preclinical and eariy phase 1 clinical data to NIDA and pharmaceutical industry partners on novel compounds for cocaine use disorder The lack of thorough characterization of compounds prior to large-scale clinical trials is least part of the reason for the large number of negative clinical trials for CocUD (Vocci and Elkashef, 2005). The initial compounds proposed for study in the center were chosen based on 1) preclinical and genetic data from our group and others supporting these classes of medications, and 2) the fact that these compounds are either available for human use currently [the selective serotonin 5-HT2C receptor (5-HT2cR) agonist lorcaserin] or are close to FDA approval [the selective serotonin 5-HT2A receptor (5-HT2AR) antagonist pimavanserin]. Lorcaserin and other 5-HT2cR agonists have been shown to reduce cocaine self-administration and cue reactivity in rodents (Project 3 Preliminary Data and (Anastasio et al, 2014a; Anastasio et al, 2014b; Cunningham et al, 2011; Manvich etal, 2012)). In addition there is human safety data in non-cocaine using subjects for lorcaserin as it is currently FDA approved for obesity, and there is safety data from a rodent cocaine interaction study (included in detail in Appendix), but there is no human cocaine interaction/PK data and no PD data to support potential dosages for phase II clinical trials. Likewise, there is evidence to support research on pimavanserin as a potential treatment for CocUD; other 5-HT2AR antagonists have been shown by our group and others to alter cocaine cue induced reinstatement in rodents (Nic Dhonnchadha etal, 2009; Pockros et al, 2011) and non-human primates (Murnane et al, 2013), but there is no specific data on pimavanserin. Finally, our group has shown that combining these two classes of compounds produces a synergistic effect on cocaine self-administration and cue reactivity (Cunningham et al, 2013) suggesting that combining these medications could produce a greater response with lower potential side effects than using either compound alone. Preclinical studies will be carried out to examine this potential combination pharmacotherapy treatment.